Data from two giant observational studies indicated that regular aspirin use was associated with significant decreases in colorectal cancer risk, but only for tumors containing "wild-type" BRAF sequences (adjusted hazard ratio 0.73, 95% CI 0.64-0.83), according to Andrew T. Chan, MD, MPH, of Massachusetts General Hospital in Boston, and colleagues.

Risk of colorectal cancer involving BRAF mutations did not differ significantly between aspirin users and non-users in the Nurses Health Study and the Health Professionals Follow-Up Study (adjusted HR 1.03, 95% CI 0.76-1.38), with more than 3 million person-years of data, the researchers reported in the June 26 issue of the Journal of the American Medical Association.

About 85% of the colorectal cancers seen in the two studies were of the wild-type BRAF variety, which explains why the results do not contradict those of randomized trials that had found a chemopreventive effect for aspirin use.

Chan and colleagues looked at BRAF status in connection with aspirin and colorectal cancer status because the gene also plays a role in cyclooxynase-2 activity, "suggesting that BRAF-mutant colonic cells might be less sensitive to the antitumor effects of aspirin than BRAF-wild-type neoplastic cells," they wrote.

They drew on data from some 128,000 participants in the two prospective observational studies, which began in 1980 in the case of the Nurses Health Study and 1986 for the Health Professionals study. Both studies had follow-up data on cancer incidence through July 2006 and on cancer mortality through 2011. Data in the studies also included tumor genotype status for participants.

About 40% of person-years of follow-up came from participants reporting regular aspirin use at any level. Roughly 10% of the person-years of aspirin use involved more than 14 tablets per week, study records indicated.

A total of 1,226 incident colorectal cancers were seen during follow-up in the studies, of which 182 involved mutant BRAF.

As in previous studies, the overall data pointed to a lower rate of colorectal cancer among the regular aspirin users, with a hazard ratio of 0.77 (95% CI 0.68-0.77) after adjusting for a host of risk factors such as age, sex, smoking, family history of colorectal cancer, diet, alcohol intake, exercise, and numerous others.

But the lower risk appeared to be concentrated entirely in prevention of tumors with wild-type BRAF. For these cancers, the age-adjusted risk associated with aspirin use was lower by 9.7 cases per 100,000 person-years (95% CI -12.6 to -6.7) compared with non-users.

In contrast, there was a slight, nonsignificant increase in mutant-BRAF tumor risk among aspirin users (0.7 cases per 100,000 person-years, 95% CI -0.3 to 1.7).

Chan and colleagues also found what looked like a dose-response effect for the number of weekly aspirin tablets reported by study participants and the number of years of aspirin use -- but again, only for wild-type BRAF tumors, not those marked by mutations.

For participants who took two to five aspirin tablets a week, there was only a trend toward reduced nonmutant-BRAF tumors versus non-users (adjusted HR 0.88, 95% CI 0.72-1.08).

But for those consuming more than 14 tablets per week, risk was cut by more than half (adjusted HR 0.43, 95% CI 0.25-0.75, P<0.001 for trend).

Similarly, no reduction in risk was seen for nonmutant-BRAF tumors in participants taking aspirin regularly for one to five years, but the reduction was large and significant for those using aspirin for more than 10 years (adjusted HR 0.66, 95% CI 0.55-0.80, P<0.001 for trend).

There were only very weak, nonsignificant trends toward reduced risk of mutant-BRAF cancers with increasing aspirin dosage and duration of use, the researchers reported.

Importantly, Chan and colleagues indicated, these patterns were independent of other molecular risk factors associated with colorectal cancer, including COX-2 expression and mutations in the PIK3CA and KRAS genes.

In an accompanying editorial, Boris Pasche, MD, PhD, of the University of Alabama at Birmingham, commented that the study provides strong clues toward aspirin's mode of action in preventing colorectal cancers.

"These findings suggest that the colorectal cancer preventive effect of aspirin in healthy individuals is predominantly mediated by its action on the RAS-RAF-MEK-ERK signaling pathway," he wrote.

But Chan and colleagues noted that the absolute differences in colorectal cancer were relatively modest, leaving the clinical implications somewhat in doubt.

"Our results must be validated by independent studies, and further investigations are necessary to confirm the association of aspirin use with a lower risk of BRAF-wild-type cancer independent of other tumor markers," they stressed.

The study was funded by the National Institutes of Health, the Bennett Family Fund for Targeted Therapies Research, and the National Colorectal Cancer Research Alliance.

Study authors reported relationships with Bayer, Millennium, Pfizer, and Pozen. Pasche reported relationships with Novartis, Amgen Vectibix, HudsonAlpha Institute, Hirslanden, and LACORE as well as several universities and governmental organizations. He also reported two pending patent applications.

Reviewed by F. Perry Wilson, MD, MSCE Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

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